A recent report suggested that genetic variations within the TCF7L2 gene are associated with risk to develop type 2 diabetes in 3 populations. Several reports have since replicated and strongly validated these initial observations, making the search for the causal sequence variations and the mechanisms whereby TCF7L2 modulate glucose homeostasis a priority in diabetes research. Nevertheless, these reports also indicate that the causal variation is likely to be non-protein coding in nature, likely contained within a linkage disequilibrium block of 92 kb that includes introns 3 and 4 of TCF7L2, making the identification of the causative sequence variants extremely difficult. In this application, we propose to test the hypothesis that introns 3 and 4 of TCF7L2 harbor evolutionarily conserved cis-regulatory elements responsible for the tissue-specific expression patterns of this gene. We will use a combination of bioinformatic tools and in vivo mouse transgenic report assay technologies to characterize the evolutionarily conserved noncoding sequences within introns 3 and 4, and identify TCF7L2 the cis-regulatory elements that may harbor functional noncoding variation conferring risk to diabetes. These studies will identify the functional noncoding sequences that may harbor the causative variations associated with diabetes in humans and will generate critical molecular and in vivo reagents that can be used to design and test hypotheses that connect TCF7L2 biology to the risk of developing diabetes. Several studies indicate that DNA sequence variation in the TCF7L2 gene may be an important factor conferring risk to develop type 2 diabetes. Nevertheless, the DNA sequence changes are probably in regulatory elements that control where and when this gene is activated. We propose a rational strategy to identify these regulatory elements. [unreadable] [unreadable] [unreadable]